This invention is related to the fields of antimicrobial agents and the treatment of microbial infections. It is, in addition, concerned with methods for identifying antimicrobial agents and agents which facilitate the action of antimicrobial agents.
None of the information presented below is admitted to be prior art to the pending claims, but is provided only to aid the understanding of the reader.
The traditional approach to treatment of microbial infections has largely been to treat with antibiotics which either kill the microbes (microcidal) or inhibit microbial growth. These antibiotics exert their antimicrobial action both in culture (in vitro), and in an infection (in vivo). Extensive screening by the pharmaceutical industry in the last fifty years for bactericidal and bacteriostatic compounds has led to the discovery and development of large numbers of antibiotics, most of which are members of a much smaller number of structural or functional classes. Examples of those classes of antibiotics are the .beta.-lactams (which include the penicillins and cephalosporins), aminoglycosides, and glycopeptides.
However, an increasingly serious problem is the spread of broad antibiotic resistance, both geographically and in different microbial species. Antibiotic resistance is particularly notable in bacteria. Such bacterial resistance to an antibiotic(s) may be due to any of a number of mechanisms. For .beta.-lactam resistance, an important mode is the production of .beta.-lactamases. Other mechanisms which result in drug resistance include the development of altered antibiotic targets and reduced cellular uptake of the drug.
An example of the development of antibiotic resistance is the appearance of methicillin resistance in Staphylococcus aureus. Methicillin is a penicillinase-stable .beta.-lactam antibiotic often used for the treatment of penicillinase-producing strains of Staphylococcus aureus. However, methicillin-resistant S. aureus (MRSA) have acquired a methicillin-insensitive cellular target which allows bacteria to grow in the presence of the drug, and the incidence of MRSA infections has become a serious problem (Chambers, Clin. Microb. Rev. 1:173-186, 1988; De Lencastre et al., J. Antimicrob. Chemother. 33:7-24, 1994). The current average incidence of MRSA in some, large hospitals in the USA increased from 8% in 1986 to 40% in 1992, and there are MRSA strains which are susceptible to only a single class of clinically available antibiotics, the glycopeptides. There is a need for the discovery of new efficient anti-MRSA drugs before resistance to glycopeptide antibiotics develops in multi-resistant MRSA strains.
The problems associated with antibiotic resistant bacteria are not limited to S. aureus, but are present in a large number of bacterial pathogens. Therefore, there is a need for the development of new types of antibacterial agents, including ones directed to new targets. Such new antibacterial agents will not only reduce the problems associated with treating infections involving resistant bacteria, but can also provide additional therapeutic options even for treating bacteria which are still susceptible to currently available antibacterial agents.
One approach to developing such new antibacterial agents is to target bacterial pathogenesis. The bacterial products related to pathogenesis are often termed "virulence factors". Virulence factors are those biological molecules produced by a pathogenic bacterium that are essential for survival in the host organism but are not necessarily essential in vitro (where survival is meant to connote entry, attachment, evasion of host immune system, nutrient acquisition, and any other molecular processes necessary for adaptation to the host environment). Since most screening for novel antibiotics has been performed in vitro, virulence factors remain unexploited targets for antibiotic discovery screens. Based on estimates from other pathogenic organisms, the number of such virulence genes in Staphylococcus aureus is estimated to be 50-100 (see, Groisman and Ochman, Trends in Microbiol. Sci. 2:289-294 (1994); Muhldorfer and Hacker, Microb. Pathogenesis 16:171-181 (1994)).